PROJECT SUMMARY Transition-metal-catalyzed cross-coupling reactions are among the most important methods for the synthesis of pharmaceuticals and enable facile preparation of molecules essential for synthetic chemistry, medicinal chemistry and pharmaceutical purposes. Further advancement in the field of cross-coupling is closely tied to (1) the development of new cross-coupling precursors, and (2) the design of new highly active catalysts that allow rapid access to important pharmaceutically relevant structural motifs. Accordingly, the purpose of this work is two-fold: (1) to develop a valuable new reaction manifold of carboxylic acids that permits ready access to metal electrophiles from ubiquitous carboxylic acids, and (2) to develop new classes of well-defined metal catalysts based on NHC ligands (NHC = N-heterocyclic carbene). Work in this laboratory over the last four years has introduced new methods for the direct cross- coupling of amide bonds in a range of generic transition-metal catalyzed cross-couplings using Pd, Rh and Ni catalysis. These methods permit direct engagement of one of the most fundamental bonds in chemistry, namely, the amide linkage, in cross-coupling reactions of high value. Furthermore, research in this laboratory has demonstrated metal-NHC catalysts as highly reactive catalysts in activating traditionally inert acyl bonds. Importantly, this permits conceptualization of a cross-coupling concept between amides and esters. Broadly speaking, the goal of our research for the next five years is to develop new methods that allow direct engagement of ubiquitous carboxylic acids in cross-coupling reactions of high synthetic value. In this reactivity manifold, the ubiquitous carboxylic acid moiety serves as an equivalent of aryl halide or pseudohalide by exploiting the oxidative addition/decarbonylation pathway. Although carboxylic acids are among the most important motifs in organic synthesis, biologically active compounds and pharmaceuticals, their cross-coupling with a concomitant loss of carbon dioxide is inherently limited by the use of expensive oxidants, harsh conditions and specific substitution patterns. This prohibits generality stemming from the rational control of elementary steps in the catalytic cycle. As a second general goal of our research, we aim to develop new, rationally-designed metal-catalysts based on NHC ligands for cross-coupling reactions. Our studies will outline the synthesis and generation of highly active, electron-rich, sterically-hindered and flexible catalysts that promote a broad range of important cross-couplings by controlling elementary steps of the catalytic cycle by ligand design. The studies will involve cross-couplings that are currently beyond the scope of current methods as well as C?C, C?N and C?X cross- coupling reactions that are routinely employed in the most important pharmaceutical transformations. The new catalytic methods and catalysts targeted by our research program will significantly advance the ability of synthetic chemists to develop structural motifs for the construction of bioactive molecules.